Radiation therapy is a mainstay in the treatment of head and neck cancer, but as with all other effective cancer therapies that have been developed to date, it is frequently associated with side effects which can negatively affect the functional outcome. Commonly reported complications of radiation-induced soft tissue injury include skin retraction, contour deformities, restricted movement, and nonhealing wounds. With an increasing number of cancer survivors in the United States, preventing or reducing these detrimental sequelae has thus become a priority. But despite improved knowledge about the cellular and molecular mechanisms responsible for post-irradiation soft tissue atrophy and fibrosis, few effective treatment options currently exist. In recent years, fat grafting has become widely employed to address the soft tissue deficit following cancer resection and radiotherapy, though effectiveness of fat transfer to address post-oncologic tissue deficit may be limited by the fibroinflammatory changes and hypovascularity of the irradiated tissue bed. While, enrichment of fat with additional adipose-derived stromal cells can reduce outcome variability and enhance fat graft retention for restoration of soft tissue deficit, a large gap in understanding how this occurs still exists. Identifying how supplemental cells enhance fat graft retention through functional subpopulation analysis may facilitate development of improved treatment therapies for head and neck cancer reconstruction. Autologous fat transfer has also become recognized to possess a regenerative effect, as it has been shown to decrease pain and stiffness in scars and improve vascular networks and dermal architecture in radiation-damaged skin. How fat transfer alters the soft tissue changes induced by radiation remains unknown, but with our recent identification of site-specific fibroblast subpopulations predominantly responsible for extracellular matrix deposition in response to injury, the effect of fat transfer on the distribution and characteristics of these cells, and how this occurs, can be determined. Findings from these studies would open new avenues for investigation into specific cell-targeted strategies to reduce or prevent onset of late radiation-induced side effects. Collectively, the experiments proposed will comprehensively determine conserved mechanisms for development of radiation fibrosis and how fat transfer can both effectively restore atrophic radiated soft tissue and improve functional sequelae of radiation therapy.